Idiopathic congenital central hypoventilation syndrome (CCHS, also known as central hypoventilation syndrome, Haddad syndrome and the literary misnomer “Ondine's curse”; MIM number: 209880, date last edited Jun. 14, 2004) is an unique disorder of respiratory control [Guilleminault et al., 1982; Haddad et al., 1978; Mellins et al., 1970; Paton et al., 1989; Shannon et al., 1976; Weese-Mayer et al., 1992; Weese-Mayer et al., 1999], occurring in association with Hirschsprung disease (HSCR) [Bower et al., 1980; Commare et al., 1993; Haddad et al., 1978; Hamilton et al., 1989; Guilleminault et al., 1982; Minutillo et al., 1989; O'Dell et al., 1987; Stern et al., 1980; Verloes et al., 1993; Weese-Mayer et al., 1992], tumors of neural crest origin [Bower et al., 1980; Commare et al., 1993; Haddad et al., 1978; Swaminathan et al., 1989; Weese-Mayer et al., 1992] (neuroblastoma, ganglioneuroblastoma, ganglioneuroma), and symptoms of diffuse autonomic nervous system dysfunction (ANSD) [Weese-Mayer et al., 2001] including decreased heart rate variability [Ogawa et al., 1993; Silvestri et al., 2000; Woo et al., 1992], an attenuated heart rate response to exercise [Silvestri et al., 1995], severe constipation [Weese-Mayer et al., 1992], esophageal dysmotility/dysphagia [Faure et al., 2002], decreased perception of discomfort, pupillary abnormalities [Goldberg et al., 1996; Weese-Mayer et al., 1992], decreased perception of anxiety [Pine et al., 1994], sporadic profuse sweating, and decreased basal body temperature among others. Subsequently, symptoms of ANSD have been identified in nuclear family members of the probands with CCHS, though the relatives of the CCHS cases tend to manifest a milder spectrum of ANSD, with fewer symptoms and/or fewer systems than the cases [Weese-Mayer et al., 2001].
CCHS is thought to be genetic in origin based upon familial recurrence data, and genetic segregation analyses. Familial recurrence data include one report each of affected monozygotic female twins [Khalifa et al., 1988], sisters [Haddad et al., 1978], male-female sibs [Weese-Mayer et al., 1993], and male-female half sibs [Hamilton et al., 1989] with CCHS. More recently, a total of five women diagnosed with CCHS in their own childhoods have given birth to infants including two with definite CCHS, one with likely CCHS confounded by severe immaturity and bronchopulmonary dysplasia, and one with later onset CCHS [Silvestri et al., 2002; McQuitty personal communication; Sritippayawan et al., 2002]. A recent report of a child with CCHS born to a woman who had neuroblastoma as an infant [Devriendt et al., 2000] provides additional evidence for a transmitted genetic component in the phenotypic spectrum of ANSD and CCHS. Further, ANSD has been studied in a case-control family design, including families ascertained through a CCHS-affected child and families of matched controls. Segregation analysis of a quantitative ANSD trait in such families found that the best-fitting model for ANSD was codominant Mendelian inheritance of a major gene [Marazita et al., 2001]. These results support the prior hypothesis that CCHS is the most severe manifestation of a general ANS dysfunction. [Weese-Mayer et al., 1993].
Pursuit of the genetic basis for CCHS by molecular genetic analysis has been limited due to the rarity of the disease (likely fewer than 400 cases worldwide). To date, most studies have also been limited to the study of genes known to be related to Hirschsprung disease. Thus far, three discrete variants which alter a single amino acid in RET, a cell surface tyrosine kinase receptor, have been reported in three unrelated CCHS patients [Amiel et al., 1998; Sakai et al., 1998; 2001]. These alterations were also present in one or both parents for two cases. A mutation in glial cell line-derived neurotrophic factor (GDNF) was reported in another patient and his unaffected mother [Amiel et al., 1998]; a mutation in endothelin-3 was reported in a fifth patient [Bolk et al., 1996]; and a mutation in brain-derived neurotrophic factor [Weese-Mayer et al., 2002] was reported in a sixth patient with symptoms of ANSD in his father. Three other reports indicate an absence of RET mutations [Bolk et al., 1996] and RNX mutations [Amiel et al., 2002; Matera et al., 2002].
Unfortunately, the success of studies that have focused on genes known to be related to Hirschsprung disease has been limited. Although, there has been a report of heterozygous expansion mutations in a polyalanine tract within PHOX2b in 18 of 29 children with CCHS in France [Amiel et al., 2003]. The expansion mutations were determined by direct sequencing of the PHOX2b gene. As is well known in the art, direct sequencing is an arduous and time intensive task.
Accordingly there remains a need for a simple, efficient assay for helping to diagnose CCHS.